Phenothiazines Dopamine antagonists

Both calmodulin and a calcium- and calmodulin-dependent phosphodiesterase activity occur in dispersed bovine parathyroid cells (20.). Some of the phenothiazines blocking the dopamine receptor in this tissue inhibit the interaction between calmodulin and the calmodulin-dependent phosphodiesterase. A series of experiments have tested the possibility that calmodulin might play a role in the effects of these agents on the parathyroid gland. The dopamine antagonists examined were weak inhibitors of calmodulin-stimulated phosphodiesterase activity (Table II). 

Other neuroleptic agents such as phenothiazines, which are non-selective dopamine antagonists, can cause endocrine dysfunction as well as extrapyra-midal side effects. 

Conventional antipsychotic (neuroleptic, phenothiazine, dopamine 2 antagonist, antiemetic)... 

Dopamine antagonists (e.g., phenothiazines, haloperidol, methyidopa) Opiates Estrogens H2-antagonists (e.g., cimetidine) MAO inhibitors Dopamine agonists (e.g., levodopa, bromocriptine, pergolide, cabergoline) ... 

Calmodulin antagonists consist of the phenothiazines (trifluoperazine and chlorpromazine), local anesthetics (dibucaine), and dopamine antagonists (pimozide and haloperidol). 

B. Risk of extrapyramidal reactions may be increased in the presence of other dopamine antagonist agents (eg, haloperidol or phenothiazines). 

Phenothiazines, butyrophenones, diphenylbutylpiperidines and thioxanthenes can oppose the effects of levodopa because of their dopamine antagonist properties, causing deterioration of motor function in Parkinson s disease. The antipsychotic effects and ex-trapyramidal adverse effects of these drugs can be opposed by levodopa. Of the atypical antipsychotics, risperidone and olanzapine cause deterioration in motor function in Parkinson s disease. Ziprasidone may act similarly, and there have been reports with quetiapine. Clozapine does not have this effect. 

Neuroleptic malignant syndrome (NMS) is a rare condition associated with a reducSon in dopamine acS vily in the brain, which has occurred with a wide variety of dopamine antagonists including the phenothiazines. It is unclear what role, if any, is played by the MAOIs in the few possible cases cited here. Note that MAOIs can cause the similar serotonin syndrome, and it is important to diflerentiate between the two conditions, especially since phenothiazines would aggravate NMS, but can successfully treat the serotonin syndrome. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Phenothiazine derivatives are nonselective, competitive Dj and D2 antagonists that block dopamine activity on corresponding receptor sites. In addition, their action is... 

---